PROJECT SUMMARY/ABSTRACT Increased comorbidities associated with aging such as atherosclerotic cardiovascular disease (CVD) is an emerging problem in HIV-1 infection despite potent antiretroviral therapy (ART). Current therapies (such as statins) to treat HIV-1-related inflammation, immune activation and CVD are inadequate. Oxidative stress has a major role in HIV-1 pathogenesis and CVD but it is unlikely that antioxidants alone will be adequate therapy. Potent antioxidants that also have specific anti-inflammatory effects against pleotropic inflammatory mediators called oxidized lipids (OxPLs) may be novel therapies to improve HIV-1 related inflammation, immune activation and CVD. Unraveling how oxidized lipids affect CVD and HIV-1 pathogenesis, may contribute to development of new therapies to manage HIV-related CVD. High-density lipoproteins (HDLs) are the most powerful independent negative predictor of CVD evident in all large epidemiological studies. Apolipoprotein A-I (apoA-I), the major protein of HDL, is responsible for the much of the anti-atherogenic and anti-inflammatory properties of HDL. These effects can be mimicked by apoA-I peptides such as 4F that are promising therapy for CVD. Statins and ApoA-I have similar anti-inflammatory properties. Limited evidence from animal studies has shown that there was enhancement of the biological properties of apoA-I peptides when given with a statin. Synergy between apoA-I mimetics and statins may in part be at the level of the intestine which may be an important modulator of atherosclerosis. Monocytes/macrophages (M/M) are at the intersection between HIV-1 immunopathogenesis, gut biology, atherosclerosis. Given the complex pathogenesis of HIV-1 related CVD, it is impossible to study exact mechanisms of synergistic effects between statins and apoA-I mimetics in humans (in vivo). Established patient cohorts within UCLA and primary human cells and lipoproteins can be used as tools to study ex vivo/in vitro synergistic effects of statin and apoA-I mimetics. In this proposal using an established physiologically meaningful ex vivo model of atherosclerosis we will explore synergistic effects of statins and ApoA-I mimetics on mechanisms that determine how oxidized lipoproteins present in chronic treated HIV-1 infection directly contribute to M/M derived foam cell formation and M/M chemotaxis (Aim 1), M/M dysfunction (Aims 2) and endothelial activation (Aim 3). We will also expand our findings in vivo (Aim 3) in middle aged/older (50-70 years old) HIV+ persons on potent ART and subclinical atherosclerosis. In this group, we will explore whether compared to matched by age, ART group not on statins, participants on statins have lower plasma levels of oxidized lipoproteins and established surrogate biomarkers and molecular signatures of M/M and endothelial activation that are known to predict and/or lead to CVD. Such an approach could reduce the excess morbidity and mortality remaining despite ART in HIV-1 infected aged persons. This work is innovative, has a potential impact on public health and directly addresses research priorities regarding aging in chronic HIV.